Biology subjects

Ku, A. T.

Publications and source records attributed to Ku, A. T..

4 recordsLinked to original sources

bioRxiv2022

A genotoxic antibody drug conjugate targeting CD276/B7H3 demonstrates efficacy across multiple biomarker defined classes of treatment refractory metastatic prostate cancer

Antibody-drug conjugates (ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, conferred sensitivity and were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive(ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 wild-type ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 non-expressors governed response. Significantly, wild-type TP53 predicted non-responsiveness (7/8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.

cancer biology↗

bioRxiv2022

A cancer stem cell population underlies a multi-lineage phenotype and drug resistance in prostate cancer

PurposeTo resist lineage-dependent therapies such as androgen receptor inhibition in prostate cancer, cancer cells often adopt a stem-like state resulting in lineage-plasticity and phenotypic heterogeneity. We assessed the dynamics of lineage determination and cellular subpopulation expansion in treatment-resistant adenocarcinoma, amphicrine, and small cell neuroendocrine castrate resistant prostate cancers (CRPCs). Experimental DesignWe developed CRPC patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model harboring epigenetic driver mutations, ARID1A and ARID1B, and displaying a range of luminal and neuroendocrine phenotypes. We used single-cell RNA-seq, barcode lineage-tracing, single-cell ATAC-seq, and RNA-FISH to delineate the subpopulation structure of the heterogeneous organoids and define the lineage hierarchy, determine potential transcriptional regulators of amphicrine lineage-plasticity, and identify subpopulation-specific molecular targets for therapeutic intervention. ResultsTranscriptionally similar stem/progenitor cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that produced mainly quiescent differentiated amphicrine progeny. Amphicrine cells were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures. By contrast, adenocarcinoma CRPC had a less defined hierarchy, as progeny originated from stem/progenitor cells and self-renewing differentiated luminal cells. NEPC was composed almost exclusively of self-renewing stem/progenitor cells. Amphicrine stem cells demonstrated concurrent transcription factor activities associated with stem/progenitor, luminal epithelial and mesenchymal lineages. Finally, the amphicrine stem/progenitor subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. ConclusionsThese data illuminate distinct origins and dynamics of subtype-specific CRPC plasticity in addition to demonstrating a strategy for targeting differentiation-competent stem cells. Translational RelevanceFor advanced prostate cancer, therapeutic resistance to androgen signaling suppression increasingly involves the development of lineage plasticity. The cellular states of transition and subpopulation heterogeneity that underlie lineage-plasticity are not well understood, which is an ongoing challenge to the design of effective treatments. Using patient-derived organoid models of various CRPC lineage subtypes, we observed distinct patterns with respect to stem/progenitor activity and associated growth phenotypes. The simultaneous expression of AR-driven and neuroendocrine identities, so-called amphicrine tumors, are thought to be an early dedifferentiation stage in plasticity-mediated resistance. We observed in an epigenetically-driven, amphicrine model of CRPC that a rare but necessary bipotent stem/progenitor population is suppressed by AURKA inhibitors, leading to tumor regression, while ARPC demonstrates both self-renewing differentiated luminal cells and stem/progenitors. These data suggest that AURKA inhibition may block the amplification of a resistance dedifferentiation pathway and should be considered in combination with AR signaling inhibitors for ARPC with characteristics of lineage plasticity.

cancer biology↗

bioRxiv2022

Defining cellular population dynamics at single cell resolution during prostate cancer progression

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigated prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in vivo. We observe a dramatic expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is in part androgen responsive. Androgen independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.

cancer biology↗

bioRxiv2021

Comparison of Approaches to Transcriptomic Analysis in Multi-Sampled Tumors

Intratumoral heterogeneity is a well-documented feature of human cancers associated with outcome and treatment resistance. However, a heterogeneous tumor transcriptome contributes an unknown level of variability to analyses of differentially expressed genes that may contribute to phenotypes of interest, including treatment response. Although current clinical practice and the vast majority of research studies use a single sample from each patient, decreasing costs in sequencing technologies and computing costs have made repeated-measures analyses increasingly economical. Repeatedly sampling the same tumor increases the statistical power of differentially expressed gene analysis that is indispensable towards downstream analysis and also increases ones understanding of within-tumor variance that may affect conclusions. Here, we compared five different methods for analyzing gene expression profiles derived from repeated sampling of human prostate tumors in two separate cohorts of patients. We also benchmarked the sensitivity of generalized linear models to linear mixed models for identifying differentially expressed genes contributing to relevant prostate cancer pathways based on a ground truth model.

bioinformatics↗